| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic triple-negative breast cancer (TNBC) |
| Cáncer de mama metastásico triple negativo (TNBC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| TNBC refers to any breast cancer that does not express estrogen receptor or progesterone receptor, and does not over-express human epidermal growth factor receptor 2 |
| TNBC se refiere a cualquier cáncer de mama que no expresa el receptor de estrógenos o progesterona, y no sobreexpresa el receptor 2 del factor de crecimiento epidérmico humano |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072740 |
| E.1.2 | Term | Locally advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the efficacy of ipatasertib (ipat)+atezolizumab (atezo)+paclitaxel (pac) [triplet] compared with control arm treatment in each cohort based on investigator-assessed progression-free survival (PFS) and overall survival (OS) |
| Para evaluar la eficacia de ipatasertib (ipat)+atezolizumab (atezo)+paclitaxel (pac) triplete, en comparación con un grupo control de tratamiento en cada cohorte basada en la supervivencia libre de progresión (SLP) evaluada por el investigador y la supervivencia general (SG) |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
• Efficacy of triplet compared with control arm treatment in each cohort, based on objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR); in patients with PIK3CA/AKT1/PTEN-altered tumors in each cohort based on PFS, OS, ORR, DOR, CBR
• Patient-reported outcomes (PROs) of function, global health status (GHS)/health-related quality of life (HRQoL) associated with ipat+pac (doublet) and triplet compared to control arm; using functional, GHS/HRQoL scales of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire- Core 30 (EORTC QLQ-C30)
• Efficacy of doublet and triplet in patients with PD-L1-non-positive tumors on basis of PFS, OS, ORR
• Safety of triplet in each cohort
• Pharmacokinetics of atezo, ipat, ipat metabolite (G-0377720) in each cohort
• Immune response to atezo in each cohort |
Para evaluar:
•La eficacia del triplete en comparación con el tratamiento del grupo control en cada cohorte, según la tasa de respuesta objetiva (ORR), la duración de la respuesta (DOR), la tasa de beneficio clínico (TBC);en pacientes con tumores alterados por PIK3CA/AKT1/PTEN en cada cohorte según PFS, OS, ORR, DOR, CBR
• Resultados de la función informados por el paciente (PRO), estado de salud global (GHS) / calidad de vida relacionada con la salud (CVRS) asociada con ipat + pac (doblete) y triplete en comparación con el brazo de control; utilizando escalas funcionales, GHS / CVRS de la Organización Europea para la Investigación y Tratamiento del Cáncer, Cuestionario de Calidad de Vida - Núcleo 30 (EORTC QLQ-C30)
•Eficacia de dobletes y tripletes en pacientes con tumores PD-L1 no positivos en base a PFS, OS, ORR
•Seguridad del triplete en cada cohorte.
•Farmacocinética del metabolito atezo, ipat, ipat (G-0377720) en cada cohorte
•Respuesta inmune al atezo en cada cohorte. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Women or men, age >= 18 years
- Willingness and ability to complete all study-related assessments, including PRO assessments, in the investigator’s judgment
- Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of Cycle 1
- Life expectancy of at least 6 months
- For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 28 days after the final dose of ipat/placebo, 5 months after the final dose of atezo /placebo, and 6 months after the final dose of pac, whichever occurs later
- For men: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating sperm, with female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 28 days after the final dose of ipat /placebo, or 6 months after the final dose of pac, whichever occurs later
- For any patients enrolled in the extended enrollment phase: patient is a current resident of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry
Disease-Specific Inclusion Criteria
- Appropriate candidate for paclitaxel monotherapy (if tumor PD-L1 status is unknown; if tumor status is known to be PD-L1+, the patient should be an appropriate candidate for atezolizumab + paclitaxel)
- Histologically documented triple-negative adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to resection with curative intent
- Submittal of a formalin-fixed, paraffin-embedded tumor tissue block or a minimum of 15 freshly cut unstained, serial tumor slides from the most recently collected tumor tissue. Cytologic or fine-needle aspiration samples are not acceptable. Tumor tissue from bone metastases that is subject to decalcification is not acceptable |
Varón o mujer con >= 18 años de edad en el momento de la firma del formulario de consentimiento informado
Tener disposición y capacidad para completar todas las evaluaciones relacionadas con el estudio, incluidas las de los PRO, de acuerdo con el criterio del investigador
Presentar enfermedad medible, de acuerdo con los criterios RECIST v1.1
-Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1
-Función hematológica y de órganos adecuada, definida por los resultados de laboratorio siguientes obtenidos en los 14 días previos a la administración de la primera dosis del tratamiento del estudio el día 1 del ciclo 1
- Esperanza de vida de al menos 6 meses.
- Para las mujeres en edad fértil: acuerdo para permanecer abstinente o usar anticonceptivos, y acuerdo para abstenerse de donar óvulos, las mujeres deben permanecer abstinentes o usar métodos anticonceptivos con una tasa de fracaso de <1% por año durante el período de tratamiento y por lo menos 28 días después de la dosis final de ipat / placebo, 5 meses después de la dosis final de atezo / placebo y 6 meses después de la dosis final de pac, lo que ocurra más tarde
- Para hombres: acuerdo para permanecer abstinente o usar métodos anticonceptivos, y acuerdo para abstenerse de donar esperma, ya que las parejas pueden ser embarazadas, los hombres deben permanecer abstinentes o usar un condón más un método anticonceptivo adicional que juntos den como resultado una tasa de fracaso de < 1% por año durante el período de tratamiento y durante 28 días después de la dosis final de ipat / placebo, o 6 meses después de la dosis final de pac, lo que ocurra más tarde
- Para cualquier paciente inscrito en la fase de inscripción extendida: el paciente es un residente actual de China continental, Hong Kong o Taiwán, y de ascendencia china
Criterios de inclusión específicos de la enfermedad
-Candidatos apropiados para paclitaxel en monoterapia (si el estado de PD-L1 del tumor es desconocido; si es estado de PD-L1 del tumor es positivo, el paciente debe ser un candidato apropiado para atezolizumab+paclitaxel)
- Adenocarcinoma de mama triple negativo documentado histológicamente que está localmente avanzado o es metastásico y no es susceptible de resección con intención curativa
- Presentación de un bloque de tejido tumoral incrustado en parafina y fijado con formalina o un mínimo de 15 portaobjetos de tumor en serie sin teñir recién cortados del tejido tumoral recolectado más recientemente. Las muestras citológicas o de aspiración con aguja fina no son aceptables. El tejido tumoral de metástasis óseas que está sujeto a descalcificación no es aceptable |
|
| E.4 | Principal exclusion criteria |
-Inability to comply with study and follow-up procedures
-History of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills
-Active infection requiring systemic anti-microbial treatment-Known HIV infection and clinically significant history of liver disease consistent with Child-Pugh Class B or C
-Current treatment with anti-viral therapy for hepatitis B virus
-Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to D1 of C1 or anticipation of need for a major surgical procedure during the study
-New York Heart Association Class II, III, or IV heart failure; left ventricular ejection fraction <50%;or active ventricular arrhythmia requiring medication
-Current unstable angina or history of myocardial infarction within 6 months prior to D1 of C1
-Congenital long QT syndrome or screening QT interval corrected through use Fridericia's formula>480 ms
-Current treatment with medications used at doses known to cause clinically relevant prolongation of QT/QTc interval
-History or presence of an abnormal Electrocardiogram that is clinically significant in the investigator's opinion
-Requirement for chronic corticosteroid therapy of >10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressant agents for a chronic disease
-Treatment with approved or investigational cancer therapy within 14days prior to D1 of C1
-Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications
Disease-Specific Exclusion Criteria
-History of or known presence of brain or spinal cord metastases, as determined by computed tomography (CT) or magnetic resonance imaging evaluation during screening or prior radiographic assessments
-Known CNS disease
Known germline BRCA1/2 deleterious mutation unless the patient is not an appropriate candidate for a PARP-inhibitor
-Any previous systemic therapy for inoperable locally advanced or metastatic triple-negative adenocarcinoma of the breast
-Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 peripheral neuropathy
-Patients who have received palliative radiotherapy to peripheral sites for pain control and whose last treatment was completed 14 days prior to D1 of C1 may be enrolled in the study if they have recovered from all acute, reversible effects
-Uncontrolled pleural effusion, pericardial effusion, or ascites, tumor-related pain hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
-Malignancies other than breast cancer within 5 years prior to D1 of C1, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
Pac-Specific Exclusion Criteria
-Known hypersensitivity or contraindication to any component of the study treatments
-Grade>=2 peripheral neuropathy
Ipat-Specific Exclusion Criteria
-History of Type I or Type II diabetes mellitus requiring insulin or active inflammatory bowel disease or active bowel inflammation
-Grade>=2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia
-Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, aspergillosis, active tuberculosis, or history of opportunistic infections
-Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug
-Prior treatment with an Akt Inhibitor
Atezo -Specific Exclusion Criteria
-Active or history of autoimmune disease or immune deficiency
-History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
-Prior allogeneic stem cell or solid organ transplantation
-Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment with atezo or within 5 months after the final dose of atezo
-History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
-Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies
-Treatment with systemic immunostimulatory agents within 4weeks or 5 half-lives of the drug prior to initiation of study treatment
-Treatment with systemic immunosuppressive medication within 2weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the study |
-Incapacidad para cumplir con los procedimientos de estudio y seguimiento.
-Antecedentes de síndrome de malabsorción u otra afección que podría interferir con la absorción enteral o incapacidad o falta de voluntad para tragar píldoras
-Infección (infec) activa que requiere tratamiento (tto) antimicrobiano sistémico
-Infec por VIH y antecedentes clínicamente significativos de enfermedad (enf) hepática compatible con Child-Pugh Clase B-C
-Tto con terapia antiviral para hepatitis B
-Procedimiento quirúrgico mayor, biopsia abierta o lesión traumática significativa dentro de los 28días anteriores al D1C1 o anticipación de necesidad de un procedimiento quirúrgico mayor durante el estudio
-Insuficiencia cardíaca de clase II, III o IV de la NYHA; fracción de eyección ventricular izquierda<50%;o arritmia ventricular activa que requiere medicación
-Angina inestable actual o historia de infarto miocardio en 6meses anteriores al D1C1
-Síndrome de QT largo congénito o intervalo QT de detección corregido mediante el uso de la fórmula de Fridericia>480ms
-Tto actual con medicaciones de las que se sepa que causan prolongaciones clínicamente relevantes del intervalo QT/QTc
-Historia o presencia de un ECG anormal que es clínicamente significativo según la opinión del investigador
-Requisitos para el tto crónico con corticosteroides de>10mg de prednisona por día o 1 dosis equivalente de corticosteroides antiinflamatorios o agentes inmunosupresores para una enf crónica
-Tto con terapia contra el cáncer aprobada o en investigación en 14días anteriores al D1C1
-Cualquier otra enf,disfunción metabólica,hallazgo de exploración física o laboratorio clínico que, en opinión del investigador,ofrezca una sospecha razonable de una enf o afección que contraindique el uso de un fármaco en investigación o que pueda afectar la interpretación de los resultados o los resultados.El pac en alto riesgo de complicaciones del tto
Criterios de exclusión específicos de la enf
-Historial o presencia de metástasis en el cerebro o la méd espinal, según determinado por TC o la evaluación de imágenes por RM durante la selección o evaluaciones radiográficas anteriores
-Enf conocida del SNC
-Mutación deletérea conocida en la línea germinal BRCA1/2,a menos que el paciente no sea un candidato apropiado para inhibidores-PARP
-Cualquier terapia sistémica previa para el adenocarcinoma de mama triple-negativo localmente avanzado o metastático
-Toxicidad no resuelta,clínicamente significativa de la terapia previa, excepto para alopecia y neuropatía periférica de G1
-Pacientes que han recibido radioterapia paliativa en sitios periféricos para control del dolor cuyo último tto se completó 14días antes del D1C1 pueden inscribirse en estudio si se han recuperado de los efectos agudos y revers
-Derrame pleural no controlado,derrame pericárdico o ascitis,hipercalcemia relacionada con el dolor de tumor o hipercalcemia sintomática que requiere el uso continuo de terapia bisfosfonato
-Enf malignas distintas de cáncer de mama dentro de 5años anteriores a D1C1,excepto carcinoma in situ de cuello uterino,carcinoma de piel no melanoma o cáncer uterino etapa I
Criterios de exclusión específicos del Pac
-Hipersensibilidad conocida o contraindicación a cualquier componente de los ttos del estudio
-G>=2 neuropatía periférica
Criterios de exclusión específicos de Ipat
-Historial de diabe mellitus I o II que requiere insulina o enf inflamatoria intestinal activa o inflamación intestinal activa
-G>=2 hipercolesterolemia no controlada o no tratada o hipertrigliceridemia
-Enf pulmonar: neumonitis,enf pulmonar intersticial,fibrosis pulmonar idiopática,fibrosis quística,aspergilosis,tuberculosis activa o antecedentes de infecs oportunistas
-Tto con inhibidores fuertes de CYP3A o inductores fuertes de CYP3A dentro de 2semanas o 5semividas de eliminación de fármaco,lo más prolongado,antes del inicio del fármaco
-Tto previo con inhibidor Akt
Atezo-Criterios de exclusión específicos
-Activo o antecedentes de enf autoinmune o inmunodeficiencia
-Antecedentes fibrosis pulmonar idiopática,neumonía organizada,inducida por fármacos,idiopática o evidencia de activa en la exploración de Tomografia Comp de tórax
-Trasplante alogénico previo de células madre u órgano sólido
-Tto con una vacuna viva y atenuada dentro de las 4semanas anteriores al inicio del tto,o la anticipación de la necesidad de dicha vacuna durante el tto con atezo o dentro de los 5meses posteriores a dosis final de atezo
-Historia de reacciones anafilácticas alérgicas graves a anticuerpos quiméricos,humanizados, proteínas de fusión
-Hipersensibilidad conocida a productos de células de ovario de hámster chino o anticuerpos humanos recombinantes
-Tto con agentes inmunoestimulantes sistémicos dentro de 4semanas o 5Vm del fármaco antes de iniciar tto
-Tto con medicamentos inmunosupresores sistémicos dentro de las 2semanas al inicio tto o anticipación de necesidad de inmunosupresores sistémicos |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Investigator-assessed PFS according to RECIST v1.1
2. OS |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. ORR, DOR, CBR as determined by the investigator according to RECIST v1.1
2. Mean and mean changes from baseline score in function (role, physical) and GHS/HRQoL by assessment timepoint and between treatment arms, as measured using the Functional and the GHS/HRQoL scales of the EORTC QLQ-C30
3. PFS, OS, ORR for patients with PD-L1-non-positive tumor patients who are administered with ipat combined with pac and patients who are administered with atezo in combination with ipat and pac
PFS, OS, CBR, DOR for patients with PD-L1-non-positive and with and without PIK3CA/AKT1/PTEN-altered tumors who are administered with ipat plus pac plus atezo compared with control arm
4. Incidence and severity of adverse events, with severity determined by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0
5. Change from baseline in targeted vital signs
6. Change from baseline in targeted clinical laboratory test results
7. Plasma concentration of ipat and its metabolite (G037720) at specified timepoints
8. Serum concentration of atezo at specified timepoints
9. Prevalence of anti-drug antibodies (ADAs) to atezo at baseline and incidence of ADAs to atezo during the study |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 76 months
2. From baseline (Day 1 of Cycle 1) and Day 15 of Cycle 1 and 2; Day 1 of Cycle 3-5 and beyond, study drug discontinuation visit (SDDV) [>= 28 days after final dose], post -treatment follow-up visit
3-4. Up to 76 months
5. From baseline to SDDV
6. From baseline to 28 days after final dose
7. Day 1 and 15 of Cycle 1 Day 15 of Cycle 3
8-9. Baseline, Day 15 of Cycle 1; Day 1 of Cycle 2-4, 8, 12 and 16 and at SDDV |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Brazil |
| Canada |
| China |
| Costa Rica |
| Czech Republic |
| Finland |
| France |
| Hungary |
| India |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Poland |
| Portugal |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Switzerland |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of this study is defined as the date when the last patient, last visit occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. In addition, the Sponsor may decide to terminate the study at any time |
| El final de estudio se define como la fecha en la que se realiza el último paciente, la última visita o la fecha en que se recibe el último punto de datos requerido para el análisis estadístico o el seguimiento de seguridad del último paciente, o lo que ocurra más adelante. Además, el sponsor puede decidir terminar el estudio en cualquier momento |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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